We are interested in the genetic basis of drug induced cardiotoxicity, and how these genetic factors may underlie serious adverse drug reactions that affect a small but significant fraction of individuals, therapeutic circumstances, o both. We will conduct genomewide screens for factors affecting cardiomyocyte contractile deficit or arrhythmia caused by anthracycline and tyrosine kinase inhibitor induced contractile deficit or arrhythmia. The ultimate research goal of this project is to discover novel mechanisms, targets, and chemical structures underlying variability in drug induced cardiotoxicity. The proposed two-stage approach is to first conduct high throughput genomewide association studies in vitro using genetically diverse mouse ES derived cardiomyocytes. The genes found in those studies will be functionally validated in human IPS derived cardiomyocytes by reducing their expression via gene knockdown. This approach takes advantage of the mapping power of mouse genetics with the biological relevance of human cell responses.